Composition and/or method for preventing recurrence of stroke

ABSTRACT

By using a composition for preventing onset and/or recurrence of stroke which contains ethyl icosapentate as its effective component, onset and/or recurrence of stroke is prevented, or in particular, the onset and/or recurrence of stroke in a hyperlipidemia patient who has been treated with HMG-CoA RI, or in particular the recurrence of stroke in a patient who is beyond six months after the onset of stroke, is prevented.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.12/343,974, filed Dec. 24, 2008, now U.S. Pat. No. 8,795,308 which is aContinuation of U.S. application Ser. No. 11/486,091, filed Jul. 14,2006, now U.S. Pat. No. 7,498,359. The benefit of priority is alsoclaimed to Japanese Patent Application No. 2006-29954, filed on Feb. 7,2006. All of the above are hereby incorporated by reference.

TECHNICAL FIELD

This invention relates to compositions for preventing onset and/orrecurrence of stroke which contains at least ethyl icosapentate(hereinafter abbreviated as EPA-E), and methods for administering thecomposition to a vertebrate including human.

BACKGROUND ART

Stroke is defined as a pathological condition in which impairment ofconsciousness and neurologic symptom(s) are acutely induced by acerebrovascular disorder, such as intracerebral hemorrhage and cerebralinfarction, and according to a report published by the Ministry ofHealth, Labor and Welfare, stroke was the third popular cause of deathin Japan in 2004. Even if a patient is lucky enough to escape the death,the after effects are often so serious that the quality of life of thepatient is greatly impaired. In addition, an onset of stroke isassociated with a high risk of its recurrence. Accordingly, stroke hasbecome an issue of public concern.

A relevance of the stroke with hypertension has been known for a longtime, and blood pressure control has been advocated and practiced byusing various antihypertensives to prevent onset or recurrence of thestroke. As a result, the mortality from stroke of intracerebralhemorrhage type certainly decreased. However, with the westernization ofdiet and the resulting increase of the patients suffering from so-called“lifestyle-related diseases” such as diabetes, hyperlipidemia andhypertension, the types of stroke in Japan has changed, and today,stroke in Japan consists of about 80% by cerebral infarction, about 15%by intracerebral hemorrhage, and about 5% by subarachnoid hemorrhage. Asthe cerebral infarction is increasing in accordance with thewesternization of diet, attention has brought on the hyperlipidemiaamong the lifestyle-related diseases, and it has been advocated thatarteriosclerotic diseases, namely, myocardial infarction, cerebralinfarction, and the like, be prevented by improving cholesterol,especially the low density lipoprotein-cholesterol (LDL-C), also knownas “bad cholesterol.”

With this as a backdrop, various clinical trials (e.g. KLIS, PATE,J-LIT) using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor(HMG-CoA RI), the so-called “statin agent” having stronghypocholesterolemic action, have been conducted in Japan, and a certainefficacy of statin in preventing onset of cerebral infarction has beensuggested. However, for efficacy in secondary prevention of the stroke,namely, prevention of its recurrence, results have not so far beengratifying.

Other exemplary compounds having the action of improving hyperlipidemiaare polyunsaturated fatty acids. The polyunsaturated fatty acid isdefined as a fatty acid including two or more carbon-carbon double bondsin one molecule, and the polyunsaturated fatty acids are categorizedbased on the position of the double bond into ω-3 fatty acid, ω-6 fattyacid, and so on. The ω-3 polyunsaturated fatty acids include α-linolenicacid, icosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), andthe ω-6 polyunsaturated fatty acids include linoleic acid, γ-linolenicacid, and arachidonic acid. Polyunsaturated fatty acids are derived fromnatural products, and exhibit various actions includingantiarteriosclerotic action, platelet aggregation inhibitory action,hypolipidemic action, anti-inflammatory action, antitumor action, andcentral action, and with their high degree of safety, they areincorporated in various foods, and sold as health foods or drugs.

It has been reported that the mortality of patients with history ofmyocardial infarction was decreased by administration of a mixture ofethyl ester of EPA (EPA-E) and ethyl ester of DHA (DHA-E), the ω-3polyunsaturated fatty acids, for 3.5 years (International PatentPublication No. WO 00/48592). However, this reference does not discloseor suggest whether EPA-E or DHA-E prevents the onset and/or recurrenceof stroke.

It has been suggested that administration of a fish oil containing EPAand DHA should prevent brain damage in patients exhibitingatherosclerosis of the artery which feeds blood to the brain(International Patent Publication No. WO 03/92673). However, thisreference histologically observed plaques in carotid artery of thepatients who have undergone carotid endarterectomy, but fails todemonstrate effects on preventing brain damages and/or the onset of thestroke.

Recently, based on the results of animal experiments and small scaleclinical findings, many large scale clinical trials have been plannedand performed in order to examine whether various drugs proven to havesome effects of improving the lifestyle-related diseases are capable ofpreventing arteriosclerotic diseases in human. So far, however, theresults have not been as expected, and especially the secondaryprevention of the stroke is still in a state of trial and error.

High purity EPA-E is commercially available in Japan in the trade namesof Epadel and Epadel S (manufactured by Mochida Pharmaceutical Co.,Ltd.) as a therapeutic drug for hyperlipidemia. There has been reportedthat when such high purity EPA-E is orally administered at a dose of 600mg per administration and 3 times a day immediately after meals (whentriglyceride (TG) is abnormal, the dose was increased up to 900 mg peradministration and 3 times a day, depending on the degree of theabnormality), the serum total cholesterol (T-Cho) concentration wasreduced by 3 to 6%, and the serum TG was reduced by 14 to 20% (DrugInterview Form “EPA preparation, Epadel capsule 300,” revised in July2002 and February 2004, version 21 issued in December 2004; pp. 21-22).It has also been reported in the American College of Cardiology 2005Annual Meeting that, based on such action, the high purity EPA-E wouldbe expected to have an effect of improving cardiovascular events ofhyperlipidemia patients, and its use in combination with statin waseffective for inhibiting cardiac events in a large scale clinical trial(Medical Tribune, issue of Nov. 17, 2005, Feature Article Part 3, pp.75-76; Circulation Vol. 112 (No. 21), pp 3362-3363, 2005). However,these publications do not disclose or suggest that EPA-E prevents onsetand/or recurrence of the stroke.

SUMMARY OF THE INVENTION

In view of the situation that the stroke is still a major cause of deathand it is a serious problem that many cases of stroke are stillimpossible to be prevented by the HMG-CoA RI therapy, an object of thepresent invention is to provide a composition for preventing onsetand/or recurrence of the stroke.

In order to solve the problems as described above, the inventors of thepresent invention made an extensive study and found that EPA-E has aneffect of preventing onset and/or recurrence of stroke, and inparticular, preventing recurrence of stroke in a patient who is beyondsix months after the onset of stroke. The present invention has beencompleted on the basis of such findings. Accordingly, the presentinvention includes the following:

(1) A method for preventing recurrence of stroke, includingadministering ethyl icosapentate orally to a patient with history ofstroke at a dose of 0.3 g/day to 6.0 g/day;

(2) A method according to (1), in which the patient is beyond six monthsafter the onset of stroke;

(3) A method according to (2), in which serum TG/HDL-C ratio of thepatient is 3.75 or more;

(4) A method according to (3), in which 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor is administered to the patient incombination with the ethyl icosapentate;

(5) A method according to (3), in which the administration of the ethylicosapentate to the patient is continued for at least three years;

(6) A method according to (3), in which a composition having the ethylicosapentate at a proportion of 96.5% by weight or more in the totalcontent of fatty acids and their derivatives is administered to thepatient;

(7) A method according to (2), in which the patient suffers fromhyperlipidemia;

(8) A method according to (7), in which 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor is administered to the patient incombination with the ethyl icosapentate;

(9) A method according to (7), in which the administration of the ethylicosapentate to the patient is continued for at least three years; and

(10) A method according to (7), in which a composition having the ethylicosapentate at a proportion of 96.5% by weight or more in the totalcontent of fatty acids and their derivatives is administered to thepatient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph prepared by plotting the incidence rate of stroke on Yaxis and the time after the start of the trial on X axis, for the EPA-Egroup and the control group, in an example of the present invention.

FIG. 2 is a graph prepared by plotting the incidence rate of stroke on Yaxis and the time after the start of the trial on X axis, for the EPA-Egroup and the control group of the patients whose serum TG/HDL-C ratioat the time of registration was 3.75 or more and the serum TG value atthe time of registration was less than 400 mg/dL, in an example of thepresent invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Next, the present invention is described in detail.

A first embodiment of the present invention is related to a compositionfor preventing onset and/or recurrence of stroke, which contains atleast EPA-E as its effective component, and a method for administeringthe composition to a normal individual or a patient with history ofstroke. Alternatively, the first embodiment of the present invention isrelated to a composition for preventing onset and/or recurrence ofstroke, which contains at least EPA-E and/or DHA-E as its effectivecomponent, and a method for administering the composition to a normalindividual or a patient with history of stroke.

The stroke includes all the pathological conditions in which impairmentof consciousness and neurologic symptoms is acutely induced bycerebrovascular disorders, and examples include, in particular,intracerebral hemorrhages (hypertensive intracerebral hemorrhage, etc.),cerebral infarction, transient ischemic attack, subarachnoid hemorrhage,cerebral thrombosis (atherothrombotic cerebral infarction, etc.),cerebral embolism (cardiogenic cerebral embolism, etc.), and lacunarinfarction. The subjects for the administration include any human whoneeds prevention of the onset of the stroke, and examples include, inparticular, patients of hyperlipidemia.

While the EPA-E content in the total fatty acids of the composition andthe dose of the composition are not particularly limited as long asintended effects of the present invention are attained, high purity ofEPA-E is preferable, for example, a proportion of the EPA-E in the totalfatty acids and their derivatives is preferably 40% by weight or more,more preferably 90% by weight or more, and still more preferably 96.5%by weight or more. The daily dose of the composition in terms of EPA-Eis typically 0.3 to 6.0 g/day, preferably 0.9 to 3.6 g/day, and stillmore preferably 1.8 to 2.7 g/day. Examples of other fatty acidspreferably contained in the composition are the ω-3 polyunsaturatedfatty acids, in particular, DHA-E. When DHA-E is contained in thecomposition, while the compositional ratio of EPA-E/DHA-E, the contentof EPA-E and DHA-E (hereinafter referred to as (EPA-E+DHA-E)) in thetotal fatty acids, and the dose of EPA-E+DHA-E, are not particularlylimited as long as intended effects of the present invention areattained, the compositional ratio of EPA-E/DHA-E is preferably 0.8 ormore, more preferably 1.0 or more, and still more preferably 1.2 ormore. High purity of EPA-E and DHA-E is preferable and, for example, thecontent of EPA-E+DHA-E in the total fatty acids and their derivatives ispreferably 40% by weight or more, more preferably 80% by weight or more,and still more preferably 90% by weight or more. The daily dose in termsof EPA-E+DHA-E is typically 0.3 to 10 g/day, preferably 0.5 to 6 g/day,and still more preferably 1 to 4 g/day. The content of other long chainsaturated fatty acids is preferably low, and the content of ω-6 fattyacids, and in particular, the content of arachidonic acid, among thelong chain unsaturated fatty acids, is preferably as low as less than 2%by weight, and more preferably less than 1% by weight.

A second embodiment of the present invention is related to a compositionfor preventing onset and/or recurrence of stroke in a hyperlipidemiapatient, which contains at least EPA-E, and a method for administeringthe composition to a hyperlipidemia patient. Alternatively, the secondembodiment of the present invention is related to a composition forpreventing onset and/or recurrence of stroke in a hyperlipidemiapatient, which contains at least EPA-E and/or DIHA-E, and a method foradministering the composition to a hyperlipidemia patient.

A third embodiment of the present invention is related to a compositionfor preventing recurrence of stroke in a patient with history of stroke,which contains at least EPA-E as its effective component, and a methodfor administering the composition to a patient with history of stroke.Alternatively, the third embodiment of the present invention is relatedto a composition for preventing recurrence of stroke in a patient withhistory of stroke, which contains at least EPA-E and/or DHA-E as itseffective component, and a method for administering the composition to apatient with history of stroke.

In the second and third embodiments of the present invention, and alsoin the fourth to thirteenth embodiments of the present inventiondescribed later, preferable representatives regarding the type ofstroke, the proportion of the EPA-E in the total fatty acids, theproportion of the EPA-E+DHA-E in the total fatty acids, thecompositional ratio of EPA-E/DHA-E, the daily dose, and the proportionof the other long chain fatty acids etc., are the same as those in thefirst embodiment of the present invention as described above.

A fourth embodiment of the present invention is related to a compositionfor preventing recurrence of stroke in a patient who is beyond sixmonths after the onset of stroke, which contains at least EPA-E as itseffective component, and a method for administering the composition to apatient who is beyond six months after the onset of stroke.Alternatively, the fourth embodiment of the present invention is relatedto a composition for preventing recurrence of stroke in a patient who isbeyond six months after the onset of stroke, which contains at leastEPA-E and/or DHA-E as its effective component, and a method foradministering the composition. In this embodiment, the preferablerepresentatives regarding the type of stroke, the proportion of theEPA-E in the total fatty acids, the proportion of the EPA-E+DHA-E in thetotal fatty acids, the compositional ratio of EPA-E/DHA-E, the dailydose, and the proportion of the other long chain fatty acids, etc. arethe same as those in the first embodiment of the present invention. Thesubject for the administration is a patient who is beyond six monthsafter the latest onset of stroke and has passed the acute period of thestroke.

A fifth embodiment of the present invention is related to a compositionhaving an excellent effect of preventing recurrence of stroke after 3years from the start of its administration, which contains at leastEPA-E as its effective component, and a method for administering thecomposition to a patient with history of stroke. In fact, continuousadministration of the composition containing at least EPA-E as itseffective component to a patient with history of stroke for at least 3years reduces the incidence rate of the stroke by at least 15% at 3years from the start of the administration, and by at least 30% at 4 or5 years from the start of the administration, compared with the controlgroup with no administration of the EPA-E. In particular, when thesubject is a patient whose serum TG/HDL-C ratio is 3.75 or more, acontinuous administration of the composition containing at least EPA-Eas its effective component for at least 3 years reduces the incidencerate of the stroke by at least 20% at 3 years from the start of theadministration, and by at least 40% at 4 or 5 years from the start ofthe administration, compared with the control group with noadministration of the EPA-E. Alternatively, the fifth embodiment of thepresent invention is related to a composition having an excellent effectof preventing recurrence of stroke after 3 years from the start of itsadministration, which contains at least EPA-E and/or DHA-E as itseffective component, and a method for administering the composition to apatient with history of stroke.

A sixth embodiment of the present invention is related to a compositionfor preventing onset and/or recurrence of stroke, which contains atleast EPA-E as its effective component, and is continuously administeredto a normal individual or a patient with history of stroke for at least3 years, in combination with HMG-CoA RI. When the subject is a patientwith history of stroke, such combined use reduces the incidence rate ofthe stroke by at least 15% at 3 years from the start of theadministration, and by at least 30% at 4 or 5 years from the start ofthe administration, compared with the control group with noadministration of the EPA-E. In particular, when the subject is apatient whose serum TG/HDL-C ratio is 3.75 or more, a continuousadministration of the composition containing at least EPA-E as itseffective component in combination with HMG-CoA RI for at least 3 yearsreduces the incidence rate of the stroke by at least 20% at 3 years fromthe start of the administration, and by at least 40% at 4 or 5 yearsfrom the start of the administration, compared with the control groupwith no administration of the EPA-E. Alternatively, the sixth embodimentof the present invention is related to a composition for preventingonset and/or recurrence of stroke, which contains at least EPA-E and/orDHA-E as its effective component, and is continuously administered to anormal individual or a patient with history of stroke for at least 3years, in combination with HMG-CoA RI.

A seventh embodiment of the present invention is related to a method forpreventing onset and/or recurrence of stroke, which includescontinuously administering a composition containing at least EPA-E asits effective component to a normal individual or a patient with historyof stroke for at least 3 years. Alternatively, the seventh embodiment ofthe present invention is related to a method for preventing onset and/orrecurrence of stroke, which includes continuously administering acomposition containing at least EPA-E and/or DHA-E as its effectivecomponent to a normal individual or a patient with history of stroke forat least 3 years.

A eighth embodiment of the present invention is related to a compositionfor preventing onset and/or recurrence of stroke which contains at leastEPA-E as its effective component, and a method for administering thecomposition to a subject of a patient whose serum TG/HDL-C ratio is 1 ormore, preferably 2 or more, and more preferably 3.75 or more.Alternatively, the eighth embodiment of the present invention is relatedto a composition for preventing onset and/or recurrence of stroke whichcontains at least EPA-E and/or DHA-E as its effective component, and amethod for administering the composition to a subject of a patient whoseserum TG/HDL-C ratio is 1 or more, preferably 2 or more, and morepreferably 3.75 or more.

A ninth embodiment of the present invention is related to a compositionfor preventing recurrence of stroke in a hyperlipidemia patient, whichcontains at least EPA-E as its effective component, and a method foradministering the composition. Alternatively, the ninth embodiment ofthe present invention is related to a composition for preventingrecurrence of stroke in a hyperlipidemia patient, which contains atleast EPA-E and/or DHA-E as its effective component, and a method foradministering the composition to a hyperlipidemia patient. Thepreferable representatives regarding the type of stroke, the proportionof the EPA-E in the total fatty acids, the proportion of the EPA-E+DHA-Ein the total fatty acids, the compositional ratio of EPA-E/DHA-E, thedaily dose, and the proportion of the other long chain fatty acids etc.in the ninth embodiment of the present invention, are the same as thosein the first embodiment of the present invention.

A tenth embodiment of the present invention is related to a compositionfor preventing recurrence of stroke, which contains at least EPA-E asits effective component, and is used in combination with HMG-CoA RI; inother words, a composition to be used in combination with HMG-CoA RI forpreventing recurrence of stroke in a patient requiring HMG-CoA RI, whichcontains at least EPA-E as its effective component, and a method foradministering the composition to a patient with history of stroke.Alternatively, the tenth embodiment of the present invention is relatedto a composition for preventing recurrence of stroke, which contains atleast EPA-E and/or DHA-E as its effective component, and is used incombination with HMG-CoA RI; in other words, a composition to be used incombination with HMG-CoA RI for preventing recurrence of stroke in apatient requiring HMG-CoA RI, which contains at least EPA-E and/or DHA-Eas its effective component, and a method for administering thecomposition to a patient with history of stroke.

While the HMG-CoA RI includes everything having inhibitory action on3-hydroxy-3-methylglutaryl coenzyme A reductase, those pharmaceuticallyadministrable are preferable. An example is preferably selected from thegroup consisting of pravastatin, simvastatin, lovastatin, fluvastatin,cerivastatin, atorvastatin, pitavastatin, rosuvastatin, and salts andtheir derivatives, and more preferably, pravastatin, lovastatin,simvastatin, fluvastatin, atorvastatin, pitavastatin, or rosuvastatin,and still more preferably, pravastatin or simvastatin. Allpharmaceutically administrable salts are included in the scope of theinvention, and preferred are sodium and potassium salts such aspravastatin sodium, fluvastatin sodium, cerivastatin sodium,atorvastatin calcium, pitavastatin calcium, and rosuvastatin calcium. Inthe present disclosure, all compounds may exist in the form of a saltunless otherwise noted, and “pravastatin,” for example, also includes asalt of pravastatin.

An eleventh embodiment of the present invention is related to acomposition to be used in combination with HMG-CoA RI for preventingonset and/or recurrence of stroke in a subject of a patient whose serumTG/HDL-C ratio is 3.75 or more, which contains at least EPA-E as itseffective component; in other words, a composition to be used incombination with HMG-CoA RI for preventing recurrence of stroke in apatient requiring HMG-CoA RI whose serum TG/HDL-C ratio is 3.75 or more,which contains at least EPA-E as its effective component, and a methodfor administering the composition to a patient with history of stroke.Alternatively, the eleventh embodiment of the present invention isrelated to a composition to be used in combination with HMG-CoA RI forpreventing onset and/or recurrence of stroke in a subject of a patientwhose serum TG/HDL-C ratio is 3.75 or more, which contains at leastEPA-E and/or DHA-E as its effective component. In other words, theeleventh embodiment of the present invention is related to a compositionto be used in combination with HMG-CoA RI for preventing recurrence ofstroke in a patient requiring HMG-CoA RI whose serum TG/HDL-C ratio is3.75 or more, which contains at least EPA-E and/or DHA-E as itseffective component, and a method for administering the composition to apatient with history of stroke. Patients requiring HMG-CoA RI sufferfrom hyperlipidemia in many cases.

The compositions and the methods in the seventh to eleventh embodimentsof the present invention are preferably compositions and methods for apatient with history of stroke, and more preferably compositions andmethods for a patient beyond six months after the onset of stroke, i.e.,a patient who has passed the acute period of stroke.

A twelfth embodiment of the present invention is related to a method forpreventing onset and/or recurrence of stroke in a patient whose serumTG/HDL-C ratio is 3.75 or more, which includes administering acomposition containing at least EPA-E as its effective component to thepatient, until the TG/HDL-C ratio becomes less than 3.75, morepreferably less than 1. Alternatively, the twelfth embodiment of thepresent invention is related to a method for preventing onset and/orrecurrence of stroke in a patient whose serum TG/HDL-C ratio is 3.75 ormore, which includes administering a composition containing at leastEPA-E and/or DHA-E as its effective component to the patient, until theTG/HDL-C ratio becomes less than 3.75, more preferably less than 1.

A thirteenth embodiment of the present invention is related to use ofEPA-E in manufacture of a composition for preventing onset and/orrecurrence of stroke. Alternatively, the thirteenth embodiment of thepresent invention is related to use of EPA-E and/or DHA-E in manufactureof a composition for preventing onset and/or recurrence of stroke.

While the EPA-E content in the total fatty acids of the composition andthe dose of the composition are not particularly limited as long asintended effects of the present invention are attained, high purity ofEPA-E is preferable and, for example, a proportion of the EPA-E in thetotal fatty acids and their derivatives of the composition is preferably40% by weight or more, more preferably 90% by weight or more, and stillmore preferably 96.5% by weight or more. The daily dose of thecomposition in terms of EPA-E is typically 0.3 to 6 g/day, preferably0.9 to 3.6 g/day, and still more preferably 1.8 to 2.7 g/day. Examplesof other fatty acids preferably contained in the composition are the ω-3polyunsaturated fatty acids, in particular, DHA-E. When DHA-E iscontained in the composition, while the compositional ratio ofEPA-E/DHA-E, the content of EPA-E+DHA-E in the total fatty acids, andthe dose of EPA-E+DHA-E are not particularly limited as long as intendedeffects of the present invention are attained, the compositional ratioof EPA-E/DHA-E is preferably 0.8 or more, more preferably 1.0 or more,and still more preferably 1.2 or more. High purity of EPA-E and DHA-E ispreferable and, for example, the content of the EPA-E+DHA-E in the totalfatty acids and their derivatives is preferably 40% by weight or more,more preferably 80% by weight or more, and still more preferably 90% byweight or more. The daily dose of the composition containing DHA-E interms of EPA-E+DHA-E is typically 0.3 to 10 g/day, preferably 0.5 to 6g/day, and still more preferably 1 to 4 g/day. The content of other longchain saturated fatty acids is preferably low, and the content of ω-6fatty acids, and in particular, the content of arachidonic acid, amongthe long chain unsaturated fatty acids, is preferably as low as lessthan 2% by weight, and more preferably less than 1% by weight.

The composition of the present invention contains EPA-E and/or DHA-E andhas the effect of preventing onset and/or recurrence of stroke whenorally administered to a normal individual or a patient having the riskfactor for stroke such as hyperlipidemia, diabetes, and hypertension. Inparticular, the composition of the present invention has the effect ofpreventing onset and/or recurrence of stroke in a hyperlipidemia apatient who has been treated with HMG-CoA RI. The composition of thepresent invention also has a combined effect when used in combinationwith HMG-CoA RI, and accordingly, onset and/or recurrence of stroke canbe even more effectively prevented by the combined use.

The composition of the present invention may be appropriately used incombination with at least a drug commonly used for preventing onsetand/or recurrence of stroke, which is, for example, selected from thegroup including antiplatelets such as aspirin, ticlopidine, clopidogrel,and cilostazol; anticoagulants such as warfarin, heparin, andximelagatran; antihypertensives such as angiotensin II receptorantagonists (candesartan, losartan, etc.), angiotensin converting enzymeinhibitors, calcium channel antagonists (amlodipine, cilnidipine, etc.),and α-1 blockers; drugs for diabetes or for improving abnormal glucosetolerance such as α-glucosidase inhibitors (voglibose, acarbose, etc.),biguanides, thiazolidinediones (pioglitazone, rosiglitazone,rivoglitazone, etc.), and fast-acting insulin secretagogues(mitiglinide, nateglinide, etc.); and antihyperlipidemics such as theHMG-CoA RI described above, fibrates, squalene synthase inhibitors(TAK-475, etc.), and cholesterol absorption inhibitors (ezetimibe,etc.). It is noted that the composition of the present invention can beused in a package together with at least one drug such as HMG-CoA RIand/or others for improving convenience.

The composition of the present invention contains less impurities suchas saturated fatty acids and arachidonic acid which are unfavorable forstroke compared to fish oil or fish oil concentrate, and its intendedeffects can be attained without causing problems such as overnutritionand excessive intake of vitamin A. In addition, since the effectivecomponent of the present composition is an ester and thus more stableagainst oxidation compared to the fish oil etc. which are essentially inthe form of triglyceride, a sufficiently stable composition can beproduced by adding a conventional antioxidant. Therefore, the use of theEPA-E has enabled production of a composition for preventing onsetand/or recurrence of stroke which can be used in clinical practice, forthe first time.

In the present specification, the term “icosapentate” designatesall-cis-5,8,11,14,17-icosapentaenoic acid.

In the present specification, the term “stroke” is defined as apathological condition in which impairment of consciousness andneurologic symptom(s) are acutely induced by a cerebrovascular disorder,which includes intracerebral hemorrhages (hypertensive intracerebralhemorrhage, etc.), cerebral infarction, transient ischemic attack,subarachnoid hemorrhage, cerebral thrombosis (atherothrombotic cerebralinfarction, etc.), cerebral embolism (cardiogenic cerebral embolism,etc.), and lacunar infarction.

In the present specification, the term “hyperlipidemia patient”designates a patient experiencing either an increase in serum T-Choconcentration, an increase in serum LDL-Cho concentration, a decrease inserum HDL-Cho concentration, or an increase in serum TG. In a narrowsense, the term “hyperlipidemia patient” designates a patient whosuffers from any one of hypercholesterolemia (with the serum T-Choconcentration of about 220 mg/dl or higher, and in a narrower sense, 250mg/dl or higher), hyper-LDL cholesterolemia (with the serum LDL-Choconcentration of 140 mg/dl or higher), hypo-HDL cholesterolemia (withthe serum HDL-Cho concentration of less than 40 mg/dl) andhypertriglyceridemia (with the serum TG of 150 mg/dl or higher). Serumconcentration of each lipid can be measured and calculated byconventional methods, typically using blood samples collected duringfasting. The serum TG/HDL-C ratio is a value obtained by dividing theserum concentration of triglyceride (TG) by the serum concentration ofhigh density lipoprotein-cholesterol (HDL-C).

TG/HDL-C ratio is known to have an inverse correlation with particlediameter of LDL according to a report for subjects of normal individualsby Maruyama et al. (J. Atheroscler. Thromb., Vol. 10, pp. 186-191,2003), in which the correlation was so found as the LDL particlediameter is 25.5 nm when TG/HDL-C ratio is 1. Among LDLs, small denseLDL (sdLDL) with the particle diameter of 25.5 nm or less, also known as“super-bad cholesterol” has a strong effect to induce arteriosclerosis,and thus the TG/HDL-C ratio has recently drawn attentions as one of thecriteria for the prognosis of arteriosclerotic diseases. According tothe correlation mentioned above, the sdLDL starts to appear when theTG/HDL-C ratio becomes 1 or more, whereby increasing the risk forarteriosclerotic diseases. Thus the cut-off value for the serum TG/HDL-Cratio is set to 3.75 in the present invention based on the referencevalue of 150 mg/dl for the TG and the reference value of 40 mg/dl forHDL-C. Patients whose serum TG/HDL-C ratio are 3.75 or more have highserum sdLDL concentration, and are predicted to have a high risk foronset of stroke. Both the high TG value and the low HDL-C are consideredas the risk factors for the arteriosclerotic diseases. However, when theTG is 400 mg/dl or more, chylomicronemia would be suspected, butchylomicronemia is considered not to be arteriosclerotic. In view ofthis, when the results were analyzed based on the TG/HDL-C ratio in theembodiment of the present invention, those cases where the serum TGvalue at the time of registration was 400 mg/dL or more were excludedfrom the subjects for the analysis.

In the present specification, the term “use of EPA-E in combination withHMG-CoA RI” includes both the embodiment in which the EPA-E and theHMG-CoA RI are simultaneously administered and the embodiment in whichboth agents are separately administered. When they are simultaneouslyadministered, they may be formulated either as a single combinationdrug, or separate drugs. When they are separately administered, EPA-Emay be administered either before or after HMG-CoA RI. The dose andratio of EPA-E and HMG-CoA RI may be adequately selected.

In the present specification, the term “use of EPA-E and/or DHA-E incombination with HMG-CoA RI” include both the embodiment in which theEPA-E and/or DHA-E and the HMG-CoA RI are simultaneously administeredand the embodiment in which both agents are separately administered.When they are simultaneously administered, they may be formulated eitheras a single combined drug, or separate drugs. When they are separatelyadministered, EPA-E and/or DHA-E may be administered either before orafter the HMG-CoA RI. The dose and ratio of EPA-E and/or DHA-E andHMG-CoA RI may be adequately selected.

The composition of the present invention has the action of preventingonset and/or recurrence of the stroke by sole administration of thecomposition, and in particular, the composition is expected to have theeffect of preventing onset and/or recurrence of stroke which cannot beprevented by sole administration of HMG-CoA RI. In addition, EPA-E hasnot only the action of reducing the serum T-Cho concentration and theserum TG, but also the pharmacological actions such as suppressingplatelet aggregation based on inhibition of arachidonic acid cascade,which are different from those of HMG-CoA RI. Therefore, the action asdescribed above can also be exerted by combined administration withHMG-CoA RI.

Since EPA-E and DHA-E are highly unsaturated, inclusion of an effectiveamount of an antioxidant, such as butylated hydroxytoluene, butylatedhydroxyanisole, propyl gallate, gallic acid, and pharmaceuticallyacceptable quinone, and α-tocopherol, is preferable.

The preparation may be orally administered to a patient in a dosage formsuch as tablet, capsule, microcapsule, granules, fine granules, powder,oral liquid preparation, syrup, and jelly. Preferably, the preparationis orally administered by filling in a capsule such as soft capsule ormicrocapsule.

It is noted that the soft capsule containing high purity EPA-E (Epadeland Epadel S) are commercially available in Japan as safe therapeuticagents for arteriosclerosis obliterans and hyperlipidemia with reducedside effects, and in these products, the proportion of the EPA-E in thetotal fatty acids is at least 96.5% by weight. Soft capsule (Omacor,Ross products) containing about 46% by weight of EPA-E and about 38% byweight of DHA-E is commercially available in the U.S. and othercountries as a therapeutic agent for hypertriglyceridemia. Thesecommercial drugs may be obtained for use in the present invention.

The dose and the period of administration of the composition forpreventing onset and/or recurrence of stroke according to the presentinvention should be sufficient for the expression of the intendedaction, and may be adequately adjusted depending on, for example, thedosage form, administration route, number of doses per day, severity ofthe symptom, body weight, age, and the like. When orally administered,the composition may be administered at a dose in terms of EPA-E of 0.3to 6 g/day, preferably 0.9 to 3.6 g/day, and more preferably 1.8 to 2.7g/day, and while the composition is typically administered in 3 divideddoses a day, if necessary, the composition may be administered in asingle dose or in several divided doses. The composition is preferablyadministered during or after the meal, and more preferably, immediately(within 30 minutes) after the meal. When the composition is orallyadministered, the administration period is typically at least 1 year,preferably at least 2 years, more preferably at least 3 years, and mostpreferably at least 5 years. The administration is preferably continuedas long as there is a high risk of onset and/or recurrence of stroke. Ifdesired, drug holidays of about 1 day to 3 months, preferably about 1week to 1 month, may be given.

The HMG-CoA RI to be used in combination is preferably administeredaccording to the recommended dosage regimen, and the dose may beadequately adjusted depending on, for example, its type, dosage form,administration route, number of doses per day, severity of the symptoms,body weight, sex, age, and the like. When orally administered, theHMG-CoA RI is typically administered at a dose of 0.05 to 200 mg/day,and preferably 0.1 to 100 mg/day in 2 to 3 divided doses a day, but ifdesired, it may be administered in a single dose or in several divideddoses. The dose of the HMG-CoA RI may be reduced depending on the doseof the EPA-E.

It is noted that pravastatin sodium (Mevalotin™ tablets and finegranules, Sankyo Co., Ltd.), simvastatin (Lipovas™ tablets, BanyuPharmaceutical Co., Ltd.), fluvastatin sodium (Lochol™ tablets, NovartisPharma K.K. and Tanabe Seiyaku Co., Ltd.), atorvastatin calcium hydrate(Lipitor™ tablets, Astellas Pharma Inc. and Pfizer), pitavastatincalcium (Livalo™ tablets, Kowa Company, Ltd. and Sankyo Co., Ltd., androsuvastatin calcium (Crestor™ tablets, AstraZeneca K.K. and Shionogi &Co., Ltd.) are commercially available in Japan as antihyperlipidemics,and lovastatin (Mevacor™ tablets, Merck) is commercially available inthe U.S. as a antihyperlipidemic. At least one of these commercial drugsmay be obtained and appropriately combined for administration accordingto the directions recommended for them.

The preferable daily doses of these drugs are, for example, 5-60 mg orpreferably 10-20 mg for pravastatin sodium, 2.5-60 mg or preferably 5-20mg for simvastatin, 10-180 mg or preferably 20-60 mg for fluvastatinsodium, 5-120 mg or preferably 10-40 mg for atorvastatin calciumhydrate, 0.5-12 mg or preferably 1-4 mg for pitavastatin calcium,1.25-60 mg or preferably 2.5-20 mg for rosuvastatin calcium, 5-160 mg orpreferably 10-80 mg for lovastatin, and 0.075-0.9 mg or preferably0.15-0.3 mg for cerivastatin, but not limited to them.

EXAMPLES

Next, the effects of the composition according to the present inventionare demonstrated by referring to Examples, which by no means limit thescope of the present invention.

Example 1 Long Term Preventive Action of EPA-E on the Onset of Stroke

Trial Procedure

This trial is a partial analysis of the results obtained in JELIS (JapanEPA Lipid Intervention Study), a large scale clinical trial of highpurity EPA preparation which was presented at the American College ofCardiology 2005 Annual Meeting. It should be noted that while aninhibitory effect of EPA on coronary events was reported in the Meeting,there was no disclosure or suggestion of its effect on stroke (forgeneral information on JELIS, see Medical Tribune, issue of Nov. 17,2005, Feature Article Part 3, pp. 75-76, and Circulation vol. 112 (No.21), pp. 3362-3363, 2005; which are incorporated herein by reference).

Specifically, of the 18,645 subject patients in the JELIS trial(hyperlipidemia patients with serum T-Cho concentration of 250 mg/dl ormore, at ages of 40 to 75 for male and postmenstrual to 75 for female;the patients within six months from the onset of stroke were excluded inorder to exclude patients in the acute period of the stroke from thetrial subjects) (EPA-E group (9,326 cases) and control group (9,319cases)), 485 subjects from the EPA-E group and 457 subjects from thecontrol group, having history of stroke (cerebral thrombosis, cerebralembolism, intracerebral hemorrhage, subarachnoid hemorrhage, andtransient ischemic attack) were observed and analyzed for the recurrenceof stroke during the period of 5 years from the start of theadministration. Further, for the cases where serum TG/HDL-C ratio wasknown (but excluding the cases where TG value was 400 mg/dl or more),results from the subjects divided into three groups based on the serumTG/HDL-C ratio at the time of registration were also analyzed. The EPA-Egroup was orally administered with Epadel (Mochida Pharmaceutical Co.,Ltd.) typically at an adult dose of 600 mg per administration and 3times a day immediately after the meal. However, in the cases havingabnormal serum TG, the dose could be increased up to 900 mg peradministration and 3 times a day, depending on the abnormality. In bothgroups, pravastatin sodium (Mevalotin™ tablets and fine granules, SankyoCo., Ltd.), simvastatin (Lipovas™ tablets, Banyu Pharmaceutical Co.,Ltd.), or atorvastatin calcium hydrate (Lipitor™ tablets, AstellasPharma Inc. and Pfizer) was used as a base drug (basal treatment), whichwas orally administered according to a predetermined dosage regimen.

Results

The number of onset (recurrence) of stroke, the incidence rate (%), andthe odds ratio for the EPA-E group in relation to the control groupduring the observation period of 5 years are shown in Table 1. The oddsratio was calculated by the equation of (incidence rate of the EPA-Egroup)/(incidence rate of the control group), and the inhibition rate ofonset of stroke was calculated by the equation of {((incidence rate ofstroke for the control group)−(incidence rate of stroke for the EPA-Egroup))/(incidence rate of stroke for the control group)}×100.

TABLE 1 Control group EPA-E group Stroke cases/All cases Strokecases/All cases Odds (incidence rate, %) (incidence rate, %) ratio48/457 33/485 0.648 (10.5) (6.8)

As a result of the EPA-E administration, the incidence rate of thestroke over 5 years in the patients who had the history of the strokewas reduced to 6.8% compared with the incidence rate of the stroke inthe control group of 10.5%. The odds ratio was 0.648, and the incidencerate of the stroke was reduced by about 35% compared with the controlgroup by the administration of EPA-E. Accordingly, the effect of EPA-Eadministration on preventing onset of stroke in patients with history ofstroke was shown.

Further, the data described above were statistically analyzed by takingbiases in the background (smoking habit, diabetes, etc.) between thegroups into consideration. FIG. 1 shows a graph depicted by plotting theincidence rate of the stroke on Y axis and the time after the start ofthe trial on X axis, and Table 2 shows the incidence rate of stroke andthe inhibition rate in the EPA-E administration group at 1 to 5 yearsafter the start of the administration.

TABLE 2 Incidence rate Incidence rate (%) in (%) in Inhibition Controlgroup EPA-E group Rate (%) After 1 year 2.0 2.1 — After 2 years 3.9 3.68 After 3 years 5.6 4.7 16 After 4 years 8.8 5.7 35 After 5 years 11.77.4 37

As demonstrated, the incidence rate of stroke was reduced by theadministration of the EPA-E, and in particular the reduction of theincidence rate of stroke was shown to be significant at 3 years or laterafter the start of the administration.

The numbers of cases in the control group and the EPA-E administrationgroup were further examined for each type of stroke, and the results forcerebral thrombosis and total of infarction type diseases are shown inTable 3. Both the number of cases and the incidence rates were alsolower for the hemorrhage type diseases in the EPA-E administrationgroup.

TABLE 3 Control group EPA-E group Stroke cases/All cases Strokecases/All cases (incidence rate, %) (incidence rate, %) Cerebral 23/45713/485 thrombosis (5.7%) (2.9%) Total of 39/457 28/485 infarctions(9.5%) (6.20)  

Similarly, for the cases where serum TG/HDL-C ratio was known (butexcluding the cases where TG value was 400 mg/dl or more), each of thethree groups of subjects, which are divided based on the serum TG/HDL-Cratio at the time of registration, was analyzed on the number of onset(recurrence) of stroke, the incidence rate (%), and the odds ratio forthe EPA-E group in relation to the control group during the observationperiod of 5 years, as shown in Table 4. The odds ratio was calculated bythe equation of (incidence rate of the EPA-E group)/(incidence rate ofthe control group), and the inhibition rate of onset of stroke wascalculated by the equation of {((incidence rate of stroke for thecontrol group)−(incidence rate of stroke for the EPA-Egroup))/(incidence rate of stroke for the control group)}×100.

TABLE 4 serum Control group EPA-E group TG/HDL-C Stroke cases/All casesStroke cases/All cases Odds ratio (incidence rate, %) (incidence rate,%) ratio Less 0/25 0/18 than 1 (0.0) (0.0) 1 to 20/223 14/244 0.640 3.75(9.0)  (5.74) 3.75 16/112 10/135 0.519 or more (14.3)  (7.4)

From the results in Table 4, there is shown a tendency that 5 the higheris the serum TG/HDL-C ratio at the time of registration, the higher isthe incidence rate of stroke. The administration of EPA-E reduced theincidence rate of stroke in the subjects with the history of strokeduring the five year period compared to the incidence rate of thecontrol group. That is, in the group where serum TG/HDL-C ratio waslower than 1, no onset of stroke was observed in both the control groupand the EPA-E group, while in the group where the serum TG/HDL-C ratioat the time of registration was 1 or more but less than 3.75, theincidence rate of stroke in the EPA-E group was 5.74%, a lower valuethan the incidence rate of stroke in the control group of 9.0%, andfurther in the group where the serum TG/HDL-C ratio at the time ofregistration was 3.75 or more, the incidence rate of stroke in the EPA-Egroup was 7.4%, a lower value than the incidence rate of stroke in thecontrol group of 14.3%. The odds ratio for these groups were 0.640 and0.519, respectively, and the incidence rate of stroke was reduced by theadministration of EPA-E by about 36% and about 48%, respectively,compared to the control group. Accordingly, the effect of theadministration of EPA-E on preventing onset and/or recurrence of strokewas found, and the results indicate that the effect of EPA-E is higherin a group where a higher risk is predicted. Further, FIG. 2 shows agraph depicted by plotting the incidence rate of the stroke in patientswhose serum TG/HDL-C ratio at the time of registration was 3.75 or moreon Y axis and the time after the start of the trial on X axis, and Table5 shows the incidence rate of stroke and the inhibition rate for theEPA-E administration group at 1 to 5 years after the start of theadministration.

TABLE 5 Incidence rate Incidence rate (%) of (%) of Inhibition Controlgroup EPA-E group Rate (%) After 1 year 1.8 1.5 17 After 2 years 6.3 2.953 After 3 years 6.3 4.4 29 After 4 years 11.6 5.2 55 After 5 years 14.27.4 48

It was found that the incidence rate of stroke was reduced by theadministration of EPA-E, and in particular the reduction of theincidence rate of stroke was shown to be significant at 3 years or laterafter the start of the administration. When compared with thechronological results of all the cases shown in Table 2, higherinhibition rates were observed at all the measuring points of 1 to 5years after the start of the administration in the patients whoseTG/HDL-C ratios were 3.75 or more, even though the group of thesepatients are predicted to have higher concentration of sdLDL, known assuper-bad cholesterol, and therefore predicted to be at higher risk foronset of stroke.

From the results as described above, the significant effect of the EPA-Eadministration on preventing onset of stroke in patients with history ofstroke was demonstrated.

INDUSTRIAL APPLICABILITY

The composition of the present invention as described above, whichcontains at least EPA-E as its effective component, is useful forpreventing onset and/or recurrence of stroke. In particular, thecomposition of the present invention is expected to be effective forpreventing onset and/or recurrence of stroke in hyperlipidemia patientswho have been treated with HMG-CoA RI, or in particular for preventingrecurrence of stroke in patients who are beyond six months after theonset of stroke. When the composition of the present invention is usedin combination with HMG-CoA RI, its effect is further synergisticallyenhanced, and such combined use is expected to further increase theeffect for preventing the onset and/or recurrence of stroke, and inparticular, for preventing recurrence of stroke in patients who arebeyond six months after the onset of stroke. Accordingly, such use ofthe present composition in combination with HMG-CoA RI is clinicallyfavorable.

1. A method for reducing recurrence of stroke, comprising administeringa composition comprising ethyl icosapentate as an effective componentthereof, orally to a patient with history of stroke at a dose of 0.3g/day to 6.0 g/day in terms of the ethyl icosapentate.
 2. A methodaccording to claim 1, wherein the patient is beyond six months after theonset of stroke.
 3. A method according to claim 2, wherein serumtriglyceride/high density lipoprotein-cholesterol (TG/HDL-C) ratio ofthe patient is 3.75 or more.
 4. A method according to claim 3, wherein3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor isadministered to the patient in combination with the compositioncomprising ethyl icosapentate.
 5. A method according to claim 3, whereinthe administration of the composition comprising ethyl icosapentate tothe patient is continued for at least three years.
 6. A method accordingto claim 3, wherein the composition comprising ethyl icosapentate isadministered to the patient at a proportion of 96.5% by weight or morein the total content of fatty acids.
 7. A method according to claim 2,wherein the patient suffers from hyperlipidemia.
 8. A method accordingto claim 7, wherein 3-hydroxy-3-methylglutaryl coenzyme A reductaseinhibitor is administered to the patient in combination with thecomposition comprising ethyl icosapentate.
 9. A method according toclaim 7, wherein the administration of the composition comprising ethylicosapentate to the patient is continued for at least three years.
 10. Amethod according to claim 7, wherein the composition comprising theethyl icosapentate is administered to the patient at a proportion of96.5% by weight or more in the total content of fatty acids.
 11. Amethod according to claim 4, wherein the 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor is simultaneously administered to thepatient with the composition comprising ethyl icosapentate as a singlecombination drug.
 12. A method according to claim 3, wherein thecomposition comprising ethyl icosapentate is administered to the patientat a proportion of 40% by weight or more in the total content of fattyacids.
 13. A method according to claim 3, wherein the compositionfurther comprises ethyl ester of docosahexaenoic acid.
 14. A methodaccording to claim 13, wherein the composition further comprisesantioxidant.
 15. A method according to claim 8, wherein the3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor issimultaneously administered to the patient with the compositioncomprising ethyl icosapentate as a single combination drug.
 16. A methodaccording to claim 7, wherein the composition comprising ethylicosapentate is administered to the patient at a proportion of 40% byweight or more in the total content of fatty acids.
 17. A methodaccording to claim 7, wherein the composition further comprises ethylester of docosahexaenoic acid.
 18. A method according to claim 17,wherein the composition further comprises antioxidant.